Are Obesity, Diabetes, and Serious Mental Illness Related?

When one is looking into the pathology of obesity and diabetes, energy regulation is an obvious place to look. For whatever reasons, the brain, body, and fat tissue aren't communicating well. This lack of appropriate energy regulation can lead to your body giving your brain signals that you are hungry even when you are full and you have a month's worth of stored fat on your belly. In the case of diabetes, poor energy regulation seems to be directly toxic to the pancreas, the organ that makes insulin. Once you lose the insulin regulation, you have developed diabetes.

A very basic lesson in biochemistry is learning about how we use food and burn it to make energy. And, indeed the biochemical reactions in some of these pathways are just gorgeous. Poetry. Glycolysis and the citric acid cycle, for example. Enter glucose and oxygen and a few other things, and exit energy in the form of ATP, flying off the citric acid cycle like sparkling droplets of water off a spinning wheel. ATP is our gasoline, and is used in every cell to power chemical reactions to keep our bodies humming along and living well.

Other biochemical cycles are also incredibly vital, but aren't quite so pretty. The folate cycle, for example, is ugly. It plays a starring role in Evolutionary Psychiatry, however, and I have to come to terms with it. There are a zillion components, an army of vitamins and end-products going every which way - amino acids, neurotransmitters, membrane lipids, and whatever homocysteine is. (Seriously - my anchor article for this post calls homocysteine a "non-protein amino acid". I'm assuming that means an amino acid that is not found in food or used to make protein chains, muscles, hair, etc., but it's not a term I'm familiar with!)

To show you a little piece of the complexity - here are some chemical reactions that are a small part of the folate cycle (Image from Wikipedia):

Homocysteine is a by-product of the folate cycle. It is supposed to be recycled back into methionine (the first molecule on the top left in the picture), but if you are low in certain B vitamins (or, like 10% of people, genetically deficient in certain enzymes that work to recycle homocysteine), you end up with too much of it hanging around. And when that happens, you have a higher risk of all sorts of nasty things, such as heart disease, stroke, hip fractures, and dementia.

A bit of biochemical nitty-gritty: turns out that homocysteine likes to cleave the disulfide bridges in cysteine molecules. That doesn't sound so bad, but it affects things you might need, like collagen, for example, which plays a major part in holding bones together and keeping your arteries nice and elastic. High homocysteine *sometimes* goes hand in hand with high triglycerides, high blood pressure (from those stiff, inelastic arteries, one would presume), low HDL (HDL is known as the "good cholesterol" carrying molecule), high fasting glucose (one of the signs of diabetes), and abdominal obesity. All those signs together, or three of them at least, anyway, make up the so-called metabolic syndrome which plagues our Western populations.

The good news is that abnormally high blood levels of homocysteine can rather easily be lowered by B vitamin supplementation. Almost any B vitamin will do the trick - B6, B12, folate, even betaine. That's rather exciting, one would think. Plausible biologic mechanism for a big, big problem. Cheap and simple fix. The bad news is that lowering homocysteine with B vitamin supplementation doesn't seem to make one whit of difference in cardiovascular disease, or at least it didn't in the 3700 Norwegian heart attack survivors who were followed for two years in the last decade (1) or seem help 5500 folks with known vascular disease or diabetes (2).

Whie I do care about your heart and bones, your brains interest me a lot more. A paper came out last year in Psychiatry Research from investigators in Croatia about high blood levels of homocysteine in patients with bipolar disorder and schizophrenia. And you will not be surprised to know that metabolic syndrome and obesity (and diabetes and heart disease) are more common in these patients than in the general population. While some of the medications used to treat these conditions definitely cause obesity and impaired glucose tolerance, when you really parse the data, there appears to be an increased risk of metabolic syndrome just from having the illnesses, apart from any medication contribution.

(A rather unrelated aside - antipsychotic medications are well known for some pretty disturbing side effects. One of the scariest ones is called "neuroleptic malignant syndrome" (NMS) where you get a high fever, stiffness, blood pressure spikes, and it can lead to kidney failure and death from muscle injury. One of the fastest treatments for NMS is electroshock therapy, believe it or not. What many people don't know is that schizophrenics institutionalized in the years prior to the invention of medication would suffer high fevers, stiffness, and death (it was called "malignant catatonia"). Now there is no question that the medicines cause NMS, but there is also an additional issue with the dopamine regulation in schizophrenia that could lead to autonomic dysfunction in a serious and fatal way. Just some food for thought.)

Right. Homocysteine. Not only does it degrade important things like bones and arteries, but it also might be able to antagonize the NMDA receptor in the brain (3), which could be a mechanism by which homocysteine itself could cause psychosis directly. It has been suggested that high homocysteine and low folate and B12 are independent risk factors for the development of schizophrenia and bipolar disorder (4).

The Croatians did a pretty simple study. They measured the fasting homocysteine and other signs of metabolic syndrome in patients admitted to their hospital ward with schizophrenia and bipolar disorder. They did not measure serum folate and B12, which is unfortunate, because that would be interesting to know. Oh well. The results? 34.2% of the sample of 60-odd patients had metabolic syndrome. And 67% of those with metabolic syndrome had high homocysteine. Only 23% of participants without high homocysteine had metabolic syndrome. In addition, high blood pressure also independently correlated with high homocysteine, which at least makes biologic sense. All in all, high homocysteine and metabolic syndrome went hand in hand with having bipolar disorder or schizophrenia in this population.

One more little interesting tidbit from the paper - high homocysteine has also been found to be correlated with high omega 6 fatty acid levels in patients with major depression. Nutrition research is extremely difficult for so many reasons - the main one being that everything is connected, and it is nearly impossible to change single variables without changing something else. We can tell that nutrition and fatty acid regulation and energy regulation are all very important in mental and physical illness - but the causes, effects, and byproducts are very difficult to sort out.

The take home? As I said in the Zombieland 2 post, I tend to connect high homocysteine levels with poor nutrition in general. Also, high homocysteine can be caused by a number of drugs and supplements, including niacin, metformin, insulin, corticosteroids, NSAIDs, and some anticonvulsants cause high homocysteine levels too. As I mentioned above, the atypical antipsychotic class of medication, very often used to treat schizophrenia and bipolar disorder can also cause obesity and diabetes. Chronic high intensity exercise and smoking are also related to high homocysteine.

What do we do about it? Having all the B vitamin players on the team can help, so it can be properly recycled. Eating leafy greens, egg yolks, and beef liver will get you plenty of B vitamins. The Norwegians in the study where B vitamin supplementation didn't help survival had already had heart attacks - the damage had already been done. Maybe homocysteine is something to keep low in the long term as a preventative strategy, or keeping homocysteine low is a good sign of good nutrition in general, leading to better health and resiliency. Lowering homocysteine did seem to reduce stroke incidence by 25% in the HOPE2 trial. For more definitive answers, we'll have to wait for more studies.

The brain is on the front lines, and metabolic syndrome (or the inflammation behind it) has psychiatric components as well. It is all linked in ways that we only barely understand.

There is a striking overlapping between substances / behaviors known to help with insulin resistance: omega 3, magnesium, chromium, b6, exercise and substance / behaviors known to help with mental health not to think that we are fundamentally talking about the same thing from two different perspectives. Moreover if you consider that too much insulin blocks the pathway from homocysteine to glutathione you can both explain hyperhomocysteinemia and the effectiveness of NAC and why vitamin b supplementation can help reduce homocysteine but just to some extent if it does not end in more glutathione production. If you push the mechanism from below with selenium you paradoxically get more insulin resistance because the demand for homocysteine drops. Add cortisol competition with vitamin d for cholesterol, vitamin d receptor polymorphisms and the different capacity most of us have to syntethize choline from veggies and you start to see a first broad coherent picture of some of the key mechanisms at stake in mental health (call it adhd in kids or depression in adults). If you push this line of reasoning even further you jump to the conclusion that the benefits of a ketogenic diet maybe are not linked to ketones at all, or indirectly through feedback signalling to stop producing the damned hormone.

I find the comment about Niacin worrying, as vitamins including Niacin are added by default to a lot of breads and cereal products here in Australia, and Vegemite is a popular default spread for many children.

What level of intake of Niacin would start to become problematic, do you think? I wonder if it is something we should be supplementing at all.